Christensenella

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1. Classification

a. Higher order taxa

Bacteria, Firmicutes, Clostridia, Clostridiales, Christensenellaceae, Christensenella

Species: Christensenella minuta, Christensenella massiliensis, Christensenella timonensis (1, 2)

2. Description and significance

Christensenella is a Gram-negative, strictly anaerobic genus of bacteria first discovered in the human gut (3). Species within this genus are bacillar (rod-shaped), non-motile and non-spore forming (3, 4, 5). Christensenella minuta, Christensenella timonensis, and Christensenella massiliensis are currently the only known species of Christensenella, all of which were isolated from human stool samples (3, 4, 5). C. minuta was first recognized as a new taxon in 2012, after a Japanese study of the human microbiome isolated a previously uncharacterized bacterial strain from a sample of human stool (3).

Christensenella in the human gut microbiome is associated with several health-promoting effects, and is believed to be strongly influenced by the genetic makeup of its host (6). As a result, it has been the focus of recent research investigating the relationship of host genetics to the development of the gut microbiome and associated implications for GI health. The presence or absence of Christensenella is thought to impact an individual’s risk of obesity. Associations with lean body type, lower BMI and reduced gain of fat tissue have highlighted possible future therapeutic uses of Christensenella (7, 8). In particular, C. minuta has been studied in obesity prevention and as a weight-loss aid (6). Christensenella is also believed to act as a keystone species (7) in the human gut, forming relationships with other bacteria which have the potential to advance scientific understanding of the role of the human gut microbiome in gastrointestinal disease (3). However, more evidence is needed in order to confirm Christensenella as a keystone species and to fully understand the structure of its genome. C. minuta is highly heritable among twins, suggesting that the human microbiome is controlled by host genetics which then indirectly influence the development of obesity and other gastrointestinal diseases through microbial pathways (6). Development of therapeutic applications for Christensenella is an area of active research (9), as are the mechanisms underlying its effects on BMI and understanding of the specific genetic elements that control its colonization of the GI tract (6).

3. Genome structure

The genomes of three known species and one unidentified strain of Christensenella have been sequenced to various assembly levels (4, 5, 10). C. massiliensis is the only species within this genus with a completely sequenced genome of 2.56 million base pairs (Mbp), 2,515 genes and 2,428 protein coding genes (5). The remaining species and strains of Christensenella have not been sequenced beyond the scaffold level (4, 10).

The genomes of taxa within the Christensenella genus are approximately 2.56 to 3.03 million base pairs (Mbp) in length and contain between 2,500 and 2,900 genes encoding between 2,403 and 2,766 proteins (4, 5, 10). Approximately 79.7% of the genome of C. minuta is comprised of functional genes (10), encoding transcription factors as well as proteins for polysaccharide biosynthesis, translation and molecular transport (1, 2). Non-coding regions of the genome are associated with tRNA, rRNA and other RNA constructs as well as several pseudogenes. Genomic GC content within this genus ranges from 50.4 to 52.1% (4, 5, 10).

As the first organism to be discovered in the Christensenella genus and the wider Christensenellaceae family, C. minuta Strain YIT 12065 is considered the founding strain of these two taxa and has served as the primary reference strain for classifying new species of Christensenella (3). Since the discovery of Strain YIT 12065, the Christensenella genus has grown to include the species C. timonensis and C. massiliensis (4, 5), which show 97.4% and 97.5% sequence similarity, respectively, with C. minuta via 16s rRNA sequencing (3, 4, 5). This degree of genetic divergence sufficiently supports their classification as novel species of Christensenella (3, 4, 5). Close relatives of Christensenella species include Caldicoprobacter oshimai (86.9% genetic concordance), Tindallia californiensis (86.3% concordance) and Clostridium ganghwense (86.1% concordance) as determined by 16s rRNA sequencing (1).

4. Cell structure

Bacteria of the Christensenella genus are short, non-motile and rod-shaped (bacillar). Single cells typically measure approx. 0.3 m x 0.8-1.9 m (3, 4, 5). C. minuta has tapered ends and may also appear in pairs with a more rounded coccobacillary shape (7). When cultured, Christensenella form circular yellow-beige colonies of 0.1-0.2 mm in diameter with a point-like appearance. Members of this genus do not form endospores (3, 4, 5).

Although Christensenella species are Gram-negative, isolates within this genus display variable Gram staining properties (7). Christensenella species were originally determined to be Gram-negative on account of the negative Gram stain observed in the initial isolate of C. minuta YIT 12065 (3). However, a Gram-positive bacterial species of similar morphology later isolated from human blood showed a 99.9% sequence similarity with C. minuta, suggesting that both Gram-positive and Gram-negative strains may exist within Christensenella and the C. minuta species (7). This variable dyeing phenomenon has also been observed among species of the order Bacillales, which similarly shows Gram-positive, Gram-negative, and Gram-variable staining. Although Christensenella is considered a Gram-negative genus, inconsistent Gram staining properties may therefore contribute to the misclassification of member species (7). LL-diaminopimelic acid, a cell wall component typically found in Gram positive bacteria, has also been identified in the cell wall of C. minuta, although this molecule has been previously observed in the cell walls of several other Gram-negative bacteria in the order Clostridiales. The cell wall of C. minuta is enriched in alanine, serine, and glutamic acid residues (3).

5. Metabolic processes

As a strictly anaerobic genus, Christensenella organisms produce energy exclusively through fermentation and contain no respiratory quinones. Bacteria of the genus Christensenella are chemoheterotrophic and saccharolytic, using glucose and other sugars including salacylin, D-xylose, L-arabinose, L-rhamnose and D-mannose as the primary energy inputs of fermentation (3). Glucose fermentation by C. minuta produces acetic acid and butyric acid. Whole-cell sugars in C. minuta include ribose, rhamnose, galactose and glucose (3). The originally characterized C. minuta strain was also capable of cellulose digestion (3). Christensenellaceae organisms are correlated with secondary bile acid metabolism (7), and may influence metabolic signaling within the human digestive system (11). C. minuta is catalase negative, oxidase negative and urease negative. It is also incapable of reducing nitrates and cannot metabolize tryptophan (3).

The role of Christensenella metabolic processes in promoting weight loss in humans is unclear, but may provide future insight into the metabolic capabilities of this genus (6).

6. Ecology

All known species of Christensenella are native to the digestive tract and have been isolated from human stool samples (3, 4, 5). Abundance of Christensenella in the gut microbiome depends on the genome of its host, as this genus shows high genetic heritability among related individuals (6). C. minuta is optimized for growth in the human digestive tract, with an optimal growth temperature of 37o-40o C (Range: 20-45o C) and an optimal pH of 7.5 (Range: 6.0 - 9.0) (3). Optimal salt concentration is roughly 1% NaCl solution. C. minuta is resistant to 20% bile (3). Heritability Christensenellaceae is a highly heritable family, meaning that similar levels of Christensenellaceae bacteria are found among related individuals, particularly twins. One study conducted at Cornell University found that microbial diversity is more similar among identical (monozygotic) compared to fraternal (dizygotic) twins, and among any twins than between two unrelated individuals (6). This effect is especially apparent for Christensenellaceae, which is present from birth. Up to 20% of species in infant stool samples collected for the study were classified as Christensenellaceae, which is a significantly higher proportion than observed in adult samples (6). As a result, the development of Christensenellaceae colonies in the gut is believed to be under the control of genes of the host individual. Christensenellaceae may therefore play a role in elucidating the effects of environmental conditions and genetic makeup on the composition of human gut microbiota and variation between individuals (6). This relationship has wide ranging implications for understanding the interdependence of genetics and the microbiome on obesity, gastrointestinal diseases and some genetic mechanisms of disease. Research into what human genes control the establishment of Christensenella is necessary to further characterize the nature and mechanisms of its relationship to its host’s genome (6). Christensenellaceae plays a role in the microbial ecology of its host and the establishment of other species within the human gut microbiome. In the human gut, the abundance of other archaeal and bacterial species is strongly associated with the presence and abundance of Christensenellaceae bacteria (6). Like Christensenellaceae, these organisms are highly heritable and may show similar linkage to the genetic makeup of the host individual. For this reason, Christensenellaceae has been proposed as a possible keystone species within the intestinal microbiome that facilitates the establishment of other microbial taxa (6).

7. Pathology

Associations with Obesity Christensenella has been found to have significant implications in the obesity phenotype. C. minuta is a point of current interest primarily because it exhibits a relationship between both host genes and host weight (6). Along with other highly heritable taxa, higher levels of Christensenellaceae member species have been observed in individuals with low BMI (<25) compared to obese individuals with a BMI > 30. C. minuta appears in higher abundance in germ-free mice receiving transplanted human feces from a lean individual compared to those receiving from an obese individual. The germ-free mice also demonstrate a lower percentage change in body weight over time (6). Additionally, mice that received a fecal transplant from an obese individual supplemented with C. minuta experienced lower gains in adipose tissue than those receiving the unaltered stool. After 21 days, these mice also weighed significantly less than those treated with unaltered stool (6). This indicates that Christensenella is involved in reducing the obesity phenotype in mammals, though its exact mechanism is not yet known.

Linkage of Christensenellaceae to obesity may be related to diet. Individuals fed a high-fat diet showed an initial increase in the stool sample abundance of Christensenellaceae after one week, but an overall reduction in abundance after four weeks on this diet (12). Conversely, obese patients fed a very low calorie diet intended to promote weight loss demonstrate an increase in the abundance of Christensenellaceae in the gut (13). A team of researchers led by Jose O. Aleman have proposed a mechanism of Christensenellaceae involvement in lipolysis which suggests that weight loss induces changes in hormonal signaling within the digestive system, in turn influencing the relative abundance and growth of weight-associated species within the gut microbiome (13).

Neurological Disease The discovery of identifiable patterns of Christensenella in the gut microbiome of individuals with Parkinson’s disease suggests that Christensenella may also play a role in the pathology of other diseases (14). Although much of the research pertaining to the human gut microbiome has been focused on its relationship to gastrointestinal diseases such as inflammatory bowel syndrome (IBS) and Crohn's disease, intestinal microbiota have been previously shown to influence neurodevelopment, modulate behavior, and contribute to neurological disorders (15). Patients with Parkinson’s disease show reduced microbiome diversity, different bacterial microbiome compositions and higher levels of Christensenella compared to non-Parkinson’s controls. This is the first evidence to potentially implicate Christensenella and other gut bacteria in the pathogenesis of Parkinson’s disease (14).

Other Implications in Human Health Centenarians and individuals older than 105 years old have been shown to have a greater prevalence and abundance of intestinal Christensenella strains. This correlation may indicate that Christensenella serves as a marker of longevity, signaling genes for longevity in the genomes of extremely old people which may also influence the abundance of this genus in the microbiota of that population (16). Additionally, a single case study in 2017 noted that C. minuta had been found in the blood of a patient suffering from acute appendicitis, suggesting that outside of the GI environment C. minuta may act as an infectious pathogen (7).

8. Current Research

Current research on the Christensenella genus is concerned with understanding its relationship with weight gain in order to construct possible interventions to treat obesity. Christensenella’s larger role in the gut microbiome has also been a focal point for understanding how it may relate to other diseases.

In a review of published research on Christensenella, the French pharmaceutical company LNC Therapeutics identified areas of disagreement regarding what an abundance of Christensenella means for an individual, and whether it acts a direct protective agent against the development of intestinal disease. Current research is focused on more precisely defining whether the presence or absence of Christensenella is an independent determinant of obesity and other associated diseases, or if a genetic predisposition towards these conditions instead influences the secondary development of Christensenella within the microbiome (9). LNC is interested in finding evidence to support previous findings that Christensenella abundance in the gut is inversely related to individual BMI. With additional support that Christensenella promotes the metabolic processes which result in low BMI, LNC aims to develop microbial therapies for treating obesity and other metabolic-related diseases (9). On October 15th, 2018, LNC obtained an exclusive patent license from Cornell University for a Christensenella-based drug (17).

Use of Christensenellaceae as a probiotic for weight maintenance following weight loss is a current focus of the Ley Lab at the Max Planck Institute for Developmental Biology (18). In addition to studying symbiosis between the microbiome and the human host, this research group is responsible for much of the early data on the heritability of Christensenella and its relationship to both human genetics and the obesity phenotype (6).

9. References

1. Sayers, E. W., Barrett, T., Benson, D. A., Bryant, S. H., Canese, K., Chetvernin, V., … Ye, J. (2009). Database resources of the National Center for Biotechnology Information. Nucleic Acids Research, 37(Database issue), D5-15. https://doi.org/10.1093/nar/gkn741

2. Benson, D. A., Karsch-Mizrachi, I., Lipman, D. J., Ostell, J., & Sayers, E. W. (2009). GenBank. Nucleic Acids Research, 37(Database issue), D26-31. https://doi.org/10.1093/nar/gkn723

3. Morotomi, M., Nagai, F. & Watanabe, Y. (2012). Description of Christensenella minuta gen. nov., sp. nov., isolated from human faeces, which forms a distinct branch in the order Clostridiales, and proposal of Christensenellaceae fam. Nov. International Journal of Systematic and Evolutionary Microbiology, 62(1), 144-149. DOI: 10.1099/ijs.0.026989-0

4. Ndongo, S., Dubourg, G., Khelaifia, S., Fournier, P.-E., & Raoult, D. (2016). Christensenella timonensis, a new bacterial species isolated from the human gut. New Microbes and New Infections, 13, 32-33. http://dx.doi.org/10.1016/j.nmni.2016.05.010

5. Ndongo, S., Khelaifia, S., Fournier, P.-E., & Raoult, D. (2016). Christensenella massiliensis, a new bacterial species isolated from the human gut. New Microbes and New Infections, 12, 69–70. https://doi.org/10.1016/j.nmni.2016.04.014

6. Goodrich, J. K., Waters, J. L., Poole, A. C., Sutter, J. L., Koren, O., Blekhman, R., … Ley, R. E. (2014). Human genetics shape the gut microbiome. Cell, 159(4), 789–799. https://doi.org/10.1016/j.cell.2014.09.053

7. Alonso, B. L., Irigoyen von Sierakowski, A., Sáez Nieto, J. A., & Rosel, A. B. (2017). First report of human infection by Christensenella minuta, a gram-negative, strickly [sic] anaerobic rod that inhabits the human intestine. Anaerobe, 44, 124–125. https://doi.org/10.1016/j.anaerobe.2017.03.007

8. Oki, K., Toyama, M., Banno, T., Chonan, O., Benno, Y., & Watanabe, K. (2016). Comprehensive analysis of the fecal microbiota of healthy Japanese adults reveals a new bacterial lineage associated with a phenotype characterized by a high frequency of bowel movements and a lean body type. BMC Microbiology, 16(284).

9. LNC Therapeutics (2018). Christensenella: the cornerstone of the gut microbiota [Press release]. Retrieved from https://lnctherapeutics.com/publications/news/christensenella-the-cornerstone-of-the-gut-microbiota/

10. Rosa, B. A., Hallsworth-Pepin, K., Martin, J., Wollam, A., & Mitreva, M. (2017). Genome sequence of Christensenella minuta DSM 22607T. Genome Announcements, 5(2), e01451-16. https://doi.org/10.1128/genomeA.01451-16

11. Ramírez-Pérez, O., Cruz-Ramón, V., Chinchilla-López, P., & Méndez-Sánchez, N. (2017). The role of the gut microbiota in bile acid metabolism. Annals of Hepatology, 16(Suppl. 1: s3-105.), s15–s20. https://doi.org/10.5604/01.3001.0010.5494

12. Lin, H., An, Y., Hao, F., Wang, Y., & Tang, H. (2016). Correlations of fecal metabonomic and microbiomic changes induced by high-fat diet in the pre-obesity state. Scientific Reports, 6. https://doi.org/10.1038/srep21618

13. Alemán, J. O., Bokulich, N. A., Swann, J. R., Walker, J. M., De Rosa, J. C., Battaglia, T., … Holt, P. R. (2018). Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women. Journal of Translational Medicine, 16. https://doi.org/10.1186/s12967-018-1619-z

14. Petrov, V.A., Saltykova, I. V., Zhukova, I. A., Alifirova, V. M., Zhukova, N. G., Dorofeeva, Y. B.,... Sazonov, A. E. (2017). Analysis of gut microbiota in patients with Parkinson’s Disease. Bulletin of Experimental Biology and Medicine, 162 (6), 734-737. http://doi.org/10.1007/s10517-017-3700-7

15. Cani, P. D. (2018). Human gut microbiome: Hopes, threats and promises. Gut, 67(9), 1716. DOI: 10.1136/gutjnl-2018-316723

16. Biagi, E., Franceschi, C., Rampelli, S., Severgnini, M., Ostan, R., Turroni, S., … Candela, M. (2016). Gut microbiota and extreme longevity. Current Biology: CB, 26(11), 1480–1485. https://doi.org/10.1016/j.cub.2016.04.016

17. LNC Therapeutics (2018, October 15). LNC Therapeutics acquires exclusive license for the Christensenella patent from Cornell University [Press release]. Retrieved from https://lnctherapeutics.com/publications/news/lnc-therapeutics-acquires-exclusive-license-for-the-christensenella-patent-from-cornell-university/

18. Ley Lab Research. (2017). Retrieved from http://www.leylab.com/index.php?id=4

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Edited by [Your Name], student of Jennifer Talbot for BI 311 General Microbiology, 2015, Boston University.